The incidence of invasive candidal infection has risen precipitously in recent years, and Candida albicans remains the dominant pathogen. Persons at risk include the neonate, the diabetic, the surgical patient, and most particularly the immunocompromised host, especially in the presence of neutropenia or the acquired immunodeficiency syndrome. The pathogenesis of invasive infection with C. albicans entails colonization of skin or mucosal surfaces and evasion of host defenses, including complement-mediated phagocytosis. Our previous work has delineated the structure-function relationships of the third component of complement (C3) in opsonization and phagocytosis. The covalent attachment of C3b to free hydroxyl or amino groups on the organism's surface constitutes the opsonic bond and is required for phagocytic recognition. Degradation of C3b to iC3b promotes phagocytosis via complement receptor type 3 (CR3) and initiates intracellular microbicidal processes. Recently, we have characterized a receptor for iC3b in cell wall, membrane, and cytosol of C. albicans which is structurally and functionally related to the alpha-chains of CR3 (more commonly known as Mac-1 or CD11b/CD18) and p150,95 (CD11c/CD18)--two members of the leukocyte adhesion glycoprotein family. The iC3b receptor in C. albicans is specifically recognized by monoclonal antibodies to alpha-chain epitopes of Mac-1 and p150,95, is of identical mass (Mr 165+15 kD), and promotes invasion by mediating adhesion to human endothelium and by inhibiting phagocytosis. Surface expression of the iC3b receptor, which is ubiquitous on clinical isolates of C. albicans, is absent in the relatively avirulent yeast Saccharomyces cerevisiae. However, S. cerevisiae possesses DNA which encodes a protein recognized by monoclonal antibodies to Mac-1 and p150,95. The derived amino acid sequence displays an overall homology of 23% with Mac-1 and p150,95 and retains an even higher homology at the putative iC3b-binding site. The iC3b receptor in yeast may thus be evolutionarily related to the leukocyte adhesion glycoproteins. In Specific Aim One, we shall expand our structural studies of the iC3b receptor in C. albicans by completing the large-scale purification of the protein and by defining its ultrastructure with immunoelectron microscopy. DNA encoding the iC3b receptor in C. albicans will be cloned by the methods employed by us with S. cerevisiae. In Specific Aim Two, we shall continue our studies of the role of the iC3b receptor in adhesion of C. albicans to human epithelium and to purified proteins from the extracellular matrix. In Specific Three, we shall use our cloned DNA from S. cerevisiae and its protein product to explore mechanisms of surface expression of the iC3b receptor in pathogenic and non-pathogenic yeasts. These studies will further our understanding of the evolution of adhesive glycoproteins in yeast and man and will help to elucidate the pathobiology of the iC3b receptor in C. albicans.